Off-Label: Spine Fusion Protein Used in Kids' Surgery

by John Fauber John Fauber,Reporter, Milwaukee Journal Sentinel/MedPage Today
October 09, 2012

An estimated 9.2% of spinal fusion surgeries in children used bone morphogenetic protein (BMP) -- a use that was not only off-label, but also costly, according to data culled from more than 8,000 pediatric spinal fusion procedures.

The median cost for spinal fusions using BMP was $47,136 versus $43,126 (P <0.001), wrote Emily Dodwell, MD, of the Hospital for Special Surgery in New York, in a research letter in the October 10 issue of the Journal of the American Medical Association.

Dodwell and colleagues analyzed data from a sample of 4,121 U.S. hospitals in the Kids' Inpatient Database.

When used in adults, BMP has been linked to a number of complications including "wound dehiscence, spinal stenosis, and respiratory stenosis" as well as the possibility that the agent is carcinogenic, but Dodwell and colleagues did not detect any significant difference in the complication rate among the 8,289 procedures in patients under the age of 18 -- 3.0% with BMP versus 3.6% without.

The authors added a cautionary note pointing out that complications reported in adults appeared late, "and would not be expected during hospitalization."

Moreover, although Dodwell conceded that the analysis was limited by a lack of longitudinal data, she concluded that BMP use in children should be stopped "until it has been shown to be safe and beneficial."

"We don't know if it is necessary or if it will present some deleterious affects," she said.

"BMP is a powerful molecular growth (agent), and its use in kids is concerning," said Sohail Mirza, MD, a professor of orthopedics at the Dartmouth Medical School. Mirza was not involved in the study.

BMP was first approved for use in spine surgery in the U.S. in 2002 based on research in adults funded by Medtronic, the company that markets a BMP-2 product called InFuse, the market-leader, which has generated sales of several hundred millions dollars a year.

Controversy has swirled around the product, Medtronic, and a group of prominent spine surgeons around the country who have received millions of dollars of payments from the company while at the same time authoring a series of papers in medical journals that touted the benefits of the product while failing to warn of serious complications.

Since 2009, investigative reports in the Journal Sentinel and MedPage Today have documented the payments as well as how some of those doctors also have conducted clinical trials of the product.

One story revealed how doctors with financial ties to Medtronic produced substantially better results with BMP in a pivotal clinical trial of the product than doctors who did not have financial conflicts. Another story found that in just 1 year Medtronic had paid more than $6 million in royalties to a handful of doctors who, over the course of 9 years, had co-authored several positive BMP papers without cautioning that it has been linked to male sterility.

Citing this series of special reports, last year the U.S. Senate Finance Committee launched an investigation into financial ties between the doctors and Medtronic.

In an email, Cindy Resman, a Medtronic spokesperson, said the company was aware of the JAMA paper, but it would not comment on it.

"The use of BMP in children is worrisome," said Richard Deyo, MD, a physician and professor with Oregon Health & Science University. ""I'd be concerned that some of the longer-term complications occasionally seen in adults – such as excessive bone growth – could occur in children. The evidence of possibly increased cancer risk with high-dose use in adults would also raise concerns in children."

Deyo, who has done research on spine surgery, was not involved in the study.

Another concern is the potential for harm when a powerful growth factor is administered into the growing bodies of children. Growth factors are proteins that occur naturally in the body that stimulate the growth of cells.

"If you want to use this in thousands and thousands of children, you need to do basic safety research," said Eugene Carragee, MD, a professor of orthopedic surgery at Stanford University in Palo Alto, Calif., who has done other research on BMP. "They are a vulnerable population."

Carragee pointed out that spinal fusion normally occurs at a much higher rate in children than adults so there should less need to use a product such as BMP in kids.

Dodwell reported grant support from the Ruth Jackson Orthopedic Society/Orthopedic Education and Research Fund. The Kids' Inpatient Database is part of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality.

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